Pyridine Krohnke

Galatsis, P. Krohnke Pyridine Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 311—313. (Review). 

In the laboratory of P. Kocovsky, novel pyridine-type P,A/-ligands were prepared from various monoterpenes. The key step was the Krohnke pyridine synthesis, and the chirality was introduced by the a,(3-unsaturated ketone component, which was derived from enantiopure monoterpenes. One of these ligands was synthesized from (+)-pinocarvone which was condensed with the acylmethylpyridinium salt under standard conditions to give good yield of the trisubstituted pyridine product. The benzylic position of this compound was deprotonated with butyllithium, and upon addition of methyl iodide the stereoselective methylation was achieved. The subsequent nucleophilic aromatic substitution (Sw/ r) gave rise to the desired ligand. 

The research team of E.-S. Lee synthesized and evaiuated severai 2,4,6-trisubstituted pyridine derivatives as potential topoisomerase I inhibitors. One of these compounds, 4-furan-2-yl-2-(2-furan-2-yl-vinyl)-6-thiophen-2-yl-pyridine, was prepared by the Krohnke pyridine synthesis and showed strong topoisomerase I inhibitory activity. 

Novel, tetrahydroquinoline-based A/,S-type ligands were prepared by the Krohnke pyridine synthesis and their... 

Krohnke pyridine synthesis Condensation of an unsaturated ketone with an a-halo ketone to give highly substituted pyridines. 254... 

Fujimori, T., Wirsching, P., Janda, K. D. Preparation of a Krohnke Pyridine Combinatorial Library Suitable for Solution-Phase Biological Screening. J. Comb. Chem. 2003, 5, 625-631. 

Keywords Krohnke pyridine, 2,4,6-triarylpyridine, ammonium acetate... 

Grosche et al. [33] established the classic Krohnke pyridine synthesis on the solid phase (Fig. 6.22 (A, B a, c)). The polymer-bound enones used in this reaction were obtained from polymer-bound acetophenones as well as polymer-bound aldehydes, thus providing enones with different substitution patterns (Fig. 6.19 (B and C)). 

The same research group accomplished a benign synthesis of Krohnke pyridines via sequential solventless aldol condensation and Michael addition (Scheme 2.2-3) [21b] these are prominent building blocks in supramolecular chemistry characterized by their jt-stacldng ability, H-bonding, and coordination. The reaction has been... 

Intramolecular KrOhnke pyridine synthesis as well as Krohnke pyridine synthesis imder microwave irradiation have also been reported. In addition, indium trichloride can be used as a catalyst in the Krdhnke pyridine synthesis. " ... 

This reaction is related to the Hantzsch Dihydropyridine Synthesis and Krohnke Pyridine Synthesis. 

This reaction is related to the Guareschi-Thorpe Pyridine Synthesis, Chichibabin Pyridine Synthesis, KrOhnke Pyridine Synthesis, and Petrenko-Kritschenko Piperidone Synthesis. 

This reaction was first reported by Krohnke et al. in 1961. It is the synthesis of 2,4,6-trisubstituted pyridine derivatives involving the formation of pyridinium ylide from pyridine and a-bromoketone, which undergoes the 1,4-Michael addition to an a, -unsaturaled compound to form 1,5-dicarbonyl compounds and cyclizes with ammonium acetate. Therefore, it is generally known as the Krohnke pyridine synthesis or Krohnke reaction. In this reaction, the intermediate 1,5-dicarbonyl compounds do not need to be isolated from reaction mixture. Because three different substituents can be introduced into pyridine ring, this reaction becomes the ideal model for combinatorial synthesis, and a library pool containing pyridine from 9 to over 200 has been generated by this reaction. 

Illustrated below is the mechanism of the Krohnke pyridine synthesis in which an ammonium ion attacks the carbonyl group close to R3. It should be pointed out that the... 

Other references related to the Krohnke pyridine synthesis are cited in the literature. ... 

The Katritzky pyridine synthesis is similar to the Krohnke pyridine synthesis, because both involve the Michael addition of a-substituted ketones 2 to a,P-unsaturated carbonyl compounds 1 in the presence of ammonium acetate, followed by the loss of the a-substituent to generate the pyridine 3. The a-substituent on the ketone in the Krohnke pyridine synthesis is typically a pyridinium salt. The a-substituent on the ketone in the Katritzky pyridine synthesis is the benzotriazolyl moiety. 

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